Metabolite Regulation of Nuclear Localization of Carbohydrate-response Element-binding Protein (ChREBP): Role of AMP as an Allosteric Inhibitor

Sato, Shogo; Jung, Hunmin; Nakagawa, Tsutomu; Pawlosky, Robert; Takeshima, Tomomi; Lee, Wan-Ru; Sakiyama, Haruhiko; Laxman, Sunil; Wynn, R. Max; Tu, Benjamin P.; MacMillan, John B.; De Brabander, Jef K.; Veech, Richard L.; Uyeda, Kosaku

doi:10.1074/jbc.M115.708982

Metabolite Regulation of Nuclear Localization of Carbohydrate-response Element-binding Protein (ChREBP): Role of AMP as an Allosteric Inhibitor

Journal Article · Wed Mar 16 00:00:00 EDT 2016 · Journal of Biological Chemistry

DOI:https://doi.org/10.1074/jbc.M115.708982· OSTI ID:1256357

Sato, Shogo ^[1]; Jung, Hunmin ^[1]; Nakagawa, Tsutomu ^[1]; Pawlosky, Robert ^[2]; Takeshima, Tomomi ^[1]; Lee, Wan-Ru ^[1]; Sakiyama, Haruhiko ^[1]; Laxman, Sunil ^[1]; Wynn, R. Max ^[1]; Tu, Benjamin P. ^[1]; MacMillan, John B. ^[1]; De Brabander, Jef K. ^[1]; Veech, Richard L. ^[2]; Uyeda, Kosaku ^[3]

Univ. of Texas Southwestern Medical Center, Dallas, TX (United States)
National Inst. on Alcohol Abuse and Alcoholism, Bethesda, MD (United States)
Univ. of Texas Southwestern Medical Center, Dallas, TX (United States); Dallas Veterans Affairs Medical Center, Dallas, TX (United States)

The carbohydrate-response element-binding protein (ChREBP) is a glucose-responsive transcription factor that plays an essential role in converting excess carbohydrate to fat storage in the liver. In response to glucose levels, ChREBP is regulated by nuclear/cytosol trafficking via interaction with 14-3-3 proteins, CRM-1 (exportin-1 or XPO-1), or importins. Nuclear localization of ChREBP was rapidly inhibited when incubated in branched-chain α-ketoacids, saturated and unsaturated fatty acids, or 5-aminoimidazole-4-carboxamide ribonucleotide. Here, we discovered that protein-free extracts of high fat-fed livers contained, in addition to ketone bodies, a new metabolite, identified as AMP, which specifically activates the interaction between ChREBP and 14-3-3. The crystal structure showed that AMP binds directly to the N terminus of ChREBP-α2 helix. Our results suggest that AMP inhibits the nuclear localization of ChREBP through an allosteric activation of ChREBP/14-3-3 interactions and not by activation of AMPK. As a result, AMP and ketone bodies together can therefore inhibit lipogenesis by restricting localization of ChREBP to the cytoplasm during periods of ketosis.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); Dept. of Veterans Affairs; Robert A. Welch Foundation

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1256357

Journal Information:: Journal of Biological Chemistry, Journal Name: Journal of Biological Chemistry Journal Issue: 20 Vol. 291; ISSN 0021-9258

Publisher:: American Society for Biochemistry and Molecular BiologyCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
59 BASIC BIOLOGICAL SCIENCES
AMP
ChREBP
allosteric regulation
glucose metabolism
glucose sensing
hepatocyte
ketogenesis
lipogenesis
nuclear localization

Metabolite Regulation of Nuclear Localization of Carbohydrate-response Element-binding Protein (ChREBP): Role of AMP as an Allosteric Inhibitor

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Cited By (7)

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